M P Akamandisa, N J Boddicker, S Yadav, C Hu, S N Hart, C Ambrosone, H Anton-Culver, P L Auer, C Bodelon, E S Burnside, F Chen, A H Eliassen, D E Goldgar, C Haiman, J M Hodge, H Huang, E M John, R Karam, J V Lacey, S Lindstroem, E Martinez, J Na, S L Neuhausen, K M O'Brien, J E Olson, T Pal, J R Palmer, A V Patel, T Pesaran, E C Polley, M E Richardson, K Ruddy, D P Sandler, L R Teras, A Trentham-Dietz, C M Vachon, C Weinberg, S J Winham, S Yao, G Zirpoli, P Kraft, J N Weitzel, S M Domchek, F J Couch, K L Nathanson
{"title":"普通人群中基因变异类型和位置与乳腺癌风险的关系","authors":"M P Akamandisa, N J Boddicker, S Yadav, C Hu, S N Hart, C Ambrosone, H Anton-Culver, P L Auer, C Bodelon, E S Burnside, F Chen, A H Eliassen, D E Goldgar, C Haiman, J M Hodge, H Huang, E M John, R Karam, J V Lacey, S Lindstroem, E Martinez, J Na, S L Neuhausen, K M O'Brien, J E Olson, T Pal, J R Palmer, A V Patel, T Pesaran, E C Polley, M E Richardson, K Ruddy, D P Sandler, L R Teras, A Trentham-Dietz, C M Vachon, C Weinberg, S J Winham, S Yao, G Zirpoli, P Kraft, J N Weitzel, S M Domchek, F J Couch, K L Nathanson","doi":"10.1016/j.annonc.2025.04.010","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk. However, it is unknown whether this risk differs by PV type or location in carriers ascertained from the general population.</p><p><strong>Patients and methods: </strong>To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2, and PALB2, we performed age adjusted case-control association analysis in 32,247 women with and 32,544 age-matched women without breast cancer from the CARRIERS Consortium. PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and P-values) using logistic regression.</p><p><strong>Results: </strong>Compared to women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex1-10 PTVs (OR=13.5, 95%CI 6.0-38.7, P<0.001) and ex13-27 PTVs (OR=9.0, 95%CI 4.9-18.5, P<0.001) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9, P=0.035; ex1-10 OR=0.5, 95%CI 0.1-1.0, P=0.065), and earlier age at breast cancer diagnosis (ex13-27 5.5 years, P<0.001; ex1-10 2.4 years, P=0.169). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort from Ambry Genetics and the population-based UK Biobank cohort. No differences in risk by gene region were observed for PTVs in other predisposition genes.</p><p><strong>Conclusion: </strong>Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced breast cancer risk, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs.</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":56.7000,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Association of Gene Variant Type and Location with Breast Cancer Risk in the General Population.\",\"authors\":\"M P Akamandisa, N J Boddicker, S Yadav, C Hu, S N Hart, C Ambrosone, H Anton-Culver, P L Auer, C Bodelon, E S Burnside, F Chen, A H Eliassen, D E Goldgar, C Haiman, J M Hodge, H Huang, E M John, R Karam, J V Lacey, S Lindstroem, E Martinez, J Na, S L Neuhausen, K M O'Brien, J E Olson, T Pal, J R Palmer, A V Patel, T Pesaran, E C Polley, M E Richardson, K Ruddy, D P Sandler, L R Teras, A Trentham-Dietz, C M Vachon, C Weinberg, S J Winham, S Yao, G Zirpoli, P Kraft, J N Weitzel, S M Domchek, F J Couch, K L Nathanson\",\"doi\":\"10.1016/j.annonc.2025.04.010\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk. However, it is unknown whether this risk differs by PV type or location in carriers ascertained from the general population.</p><p><strong>Patients and methods: </strong>To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2, and PALB2, we performed age adjusted case-control association analysis in 32,247 women with and 32,544 age-matched women without breast cancer from the CARRIERS Consortium. PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and P-values) using logistic regression.</p><p><strong>Results: </strong>Compared to women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex1-10 PTVs (OR=13.5, 95%CI 6.0-38.7, P<0.001) and ex13-27 PTVs (OR=9.0, 95%CI 4.9-18.5, P<0.001) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9, P=0.035; ex1-10 OR=0.5, 95%CI 0.1-1.0, P=0.065), and earlier age at breast cancer diagnosis (ex13-27 5.5 years, P<0.001; ex1-10 2.4 years, P=0.169). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort from Ambry Genetics and the population-based UK Biobank cohort. No differences in risk by gene region were observed for PTVs in other predisposition genes.</p><p><strong>Conclusion: </strong>Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced breast cancer risk, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs.</p>\",\"PeriodicalId\":8000,\"journal\":{\"name\":\"Annals of Oncology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":56.7000,\"publicationDate\":\"2025-04-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.annonc.2025.04.010\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.annonc.2025.04.010","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Association of Gene Variant Type and Location with Breast Cancer Risk in the General Population.
Background: Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk. However, it is unknown whether this risk differs by PV type or location in carriers ascertained from the general population.
Patients and methods: To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2, and PALB2, we performed age adjusted case-control association analysis in 32,247 women with and 32,544 age-matched women without breast cancer from the CARRIERS Consortium. PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and P-values) using logistic regression.
Results: Compared to women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex1-10 PTVs (OR=13.5, 95%CI 6.0-38.7, P<0.001) and ex13-27 PTVs (OR=9.0, 95%CI 4.9-18.5, P<0.001) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9, P=0.035; ex1-10 OR=0.5, 95%CI 0.1-1.0, P=0.065), and earlier age at breast cancer diagnosis (ex13-27 5.5 years, P<0.001; ex1-10 2.4 years, P=0.169). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort from Ambry Genetics and the population-based UK Biobank cohort. No differences in risk by gene region were observed for PTVs in other predisposition genes.
Conclusion: Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced breast cancer risk, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs.
期刊介绍：
Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine.
The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings.
Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.
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